Gastrointestinal mucosa-adherent pharmaceutical composition

ABSTRACT

In order to provide a composition having a long gastroduodenal residence time and exhibiting an improved efficacy, is provided a gastrointestinal mucosa-adherent composition comprising an active ingredient and a material which swells a viscogenic agent capable of being viscous with water a (e.g. curdlan and/or a low-substituted hydroxypropylcellulose etc.).

This is a 371 of PCT/JP98/01284 filed Mar. 24, 1998.

BACKGROUND ART

Since 1983 when Helicobacter pylori (hereinafter sometimes abbreviatedas H. Pylori or HP) was first isolated [Lancet, 1, 1273 (1983)], itsrelation to gastritis and gastrointestinal ulcer has gathered attention.This is because whereas HP is not usually found in the gastric mucus andon the gastric epithelium of healthy humans [APMIS, 96, 84 (1983)], itis detected at a high rate among patients with chronic gastritis orgastric ulcer. [Am. J. Gastroenterol., 32, 2283 (1987)].

The cure rate of gastroduodenal ulcer rose phenomenally with thedevelopment of H₂ blockers and proton pump inhibitors (briefly, PPI).However there still are refractory cases not even responding tojudicious treatments with those drugs, thus posing a serious problem.According to a report reviewing such refractory gastric ulcer cases[Japanese Journal of Gastroenterology, 89, 571 (1992)], depressions werefound in the amount of gastric mucus, because of apparently the ammoniaproduced by HP. It has also been reported that a sustained HP infectionretards healing of the ulcer or is involved in relapses of the ulcer[Lancet, 335, 1233 (1990); N. Engl. J. Med., 328, 308 (1993)].Heretofore, various drugs having anti-Helicobacter pylori activity havebeen administered to patients with gastroduodenal ulcers. For example,as antimicrobial preparations against Helicobacter pylori, amoxicillin,metronidazole, bismuth nitrate, and tetracycline are administered eitherindependently or in combination, but because their effective doses arecomparatively high (e.g. 750 mg amoxicillin or 500 mg metronidazole, tobe administered three times daily), those preparations frequently entailside effects such as diarrhea, abdominal pain, and nausea.

Meanwhile, in order to maintain its life, Helicobacter pylori is obligedto decompose urea into ammonia with the urease which it elaborates foritself. Therefore, urease inhibitors such as hydroxamic acid derivatives(the 15th Medical Chemistry Symposium, Synopsis of Lectures at the 4thAnnual Meeting of Medical Chemistry Group, page 167, P-41), a cassiabark extract [Synopsis of Lectures at the 117th Congress ofPharmaceutical Society of Japan 27 [H1] 9-5, p81 (1997)], andflurofamide [Micro. Ecol. Health Dis., 4 (Suppl.) S145 (1991)] areexpected to have anti-Helicobacter pylori activity.

For an improved expression of the efficacy of a active ingredient and areduced risk for side effects, an attempt was made to formulateamoxicillin, for instance, into a gastric mucosa-adherent composition toprolong its intragastric residence time and let amoxicillin be releasedat a controlled rate and with consequent improved availability of activeingredient (WO 94/00112). It has been demonstrated that the rate ofclearance of Helicobacter pylori can be improved by causing an anti-HPsubstance to stay in the stomach longer to ensure prolonged exposure ofthe bacteria to the active substance [Scand. J. Gastroenterol., 29,16-42 (1994)].

A combination drug delivery system has also been constructed, in whichan antimicrobial substance and/or an antiulcer substance is supplied ina gastric mucosa-adherent solid composition. It has been shown that withthis drug delivery system,,the efficacy of the antimicrobial substanceand that of the antiulcerative substance can be synergisticallyexploited (Japanese Patent Unexamined Publication No. 126189/1995).

The present invention has for its object to provide a pharmaceuticalcomposition which has enhanced mucosa-adherent activity compared withother gastric mucosa-adherent preparations, and consequently, anextremely improved efficacy of the active ingredient, in particular, ananti-Helicobacter pylori composition and a pharmaceutical preparation,for the prophylaxis, treatment or prevention of relapse ofgastroduodenal ulcers, which is very satisfactory and favorable inhaving anti-HP effect, low risk for side effects, sustained effect, andsafety.

DISCLOSURE OF INVENTION

In view of the above state of the art, the inventors of the presentinvention have discovered that the effectiveness of active ingredients(e.g. anti HP effect) can be potentiated by incorporating an agent (e.g.a curdlan and/or a low-substituted hydroxypropylcellulose) which swellsa viscogenic agent, in the objective gastrointestinal mucosa-adherentcomposition containing an active ingredient (e.g. anti HP substance),and that the composition has favorable safety characteristics and anenhanced adhesion the mucosa.

The present invention, therefore, is directed to:

(1) A gastrointestinal mucosa-adherent pharmaceutical compositioncomprising a material which swells a viscogenic agent capable of beingviscous with water(viscogenic agent),

(2) A pharmaceutical composition according to (1), wherein the materialis a curdlan and/or a low-substituted hydroxypropylcellulose,

(3) A pharmaceutical composition according to (2), which is matrixcomprising a polyglycerol fatty acid ester and/or a lipid,

(4) A pharmaceutical composition according to (3), wherein the curdlanand/or the low-substituted hydroxypropylcellulose is dispersed,

(5) A pharmaceutical composition according to (4), which is in a granuleform,

(6) A pharmaceutical composition according to (1), which is ananti-Helicobacter pylori preparation,

(7) A pharmaceutical composition according to (1), which is anantimicrobial preparation,

(8) A pharmaceutical composition according to (2), wherein thehydroxypropoxy content of the low-substituted hydroxypropylcellulose isabout 7.0 to about 13.0%,

(9) A pharmaceutical composition according to (3), wherein the lipid isa hydrogenated castor oil,

(10) A pharmaceutical composition according to (3), wherein thepolyglycerol fatty acid ester is an ester of a polyglycerol having adegree of polymerization from about 2 to about 20 with a fatty acidcontaining about 8 to about 40 carbon atoms.

(11) A pharmaceutical composition according to (3), wherein the amountof the polyglycerol fatty acid ester and/or the lipid used is about 20to about 95 weight % to the total weight of the composition,

(12) A pharmaceutical composition according to (3), wherein the amountof the polyglycerol fatty acid ester and/or the lipid used is about 0.1to about 100 times by weight to the active ingredient in thecomposition,

(13) A pharmaceutical composition according to (3), comprising aviscogenic agent in the matrix,

(14) A pharmaceutical composition according to (12), wherein the amountof the viscogenic agent used is about 0.5 to about 45 weight % to thetotal weight of the composition,

(15) A pharmaceutical composition according to (3), wherein the HLBnumber of the polyglycerol fatty acid ester is about 1 to about 9,

(16) A pharmaceutical composition according to (6), wherein the amountof the anti-Helicobacter pylori substance used is about 10 to about 50weight % to the 5 total weight of the composition,

(17) A pharmaceutical composition according to (3), wherein the matrixis coated with a coating material comprising a viscogenic agent,

(18) A pharmaceutical composition according to (13) or (17), wherein theviscogenic agent is an acrylic polymer or salt thereof,

(19) A pharmaceutical composition according to (6), wherein theanti-Helicobacter pylori substance is amoxicillin,

(20) A pharmaceutical composition according to (6), wherein theanti-Helicobacter pylori substance isN-(diaminophosphinyl)-5-methyl-2-thiophenecarboxamide,

(21) A pharmaceutical composition according to (6), wherein theanti-Helicobacter pylori substance is a tryptophanyl-t-RNA synthesisinhibitor,

(22) A pharmaceutical composition according to (6), wherein theanti-Helicobacter pylori substance is a oxazolone derivative,

(23) A pharmaceutical composition according to (6), wherein theanti-Helicobacter pylori substance is indolmycin,

(24) An accelerant of gastrointestinal mucosa-adherent activity of agastrointestinal mucosa-adherent composition, comprising a curdlanand/or a low-substituted hydroxypropylcellulose,

(25) A method to accelerate gastrointestinal mucosa-adherent activity byusing a curdlan and/or a low-substituted hydroxypropylcellulose,

(26) A use of the curdlan and/or a low-substitutedhydroxypropylcellulose as an accelerant of gastrointestinalmucosa-adherent activity of a gastrointestinal mucosa-adherentcomposition,

(27) A pharmaceutical composition according to (6), which is acomposition for the prophylaxis, treatment, or prevention of relapse ofHelicobacter pylori related disease,

(28) A pharmaceutical composition according to (3), comprising (i) thelow-substituted hydroxypropylcellulose, (ii) the acrylic polymer or saltthereof, (iii) the polyglycerol fatty acid ester and/or the lipid, and(iv) an anti-Helicobacter pylori substance,

(29) A pharmaceutical composition according to (28), wherein (i) thehydroxypropoxy content of the low-substituted hydroxypropylcellulose isabout 7.0 to about 13.0%, (ii) the molecular weight of the acrylicpolymer is about 20×10⁴ to about 600×10⁴, (iii) the polyglycerol fattyacid ester and/or the lipid is tetraglycerol polyricinolate, and (iv)the anti-Helicobacter pylori substance is indolmycin, and

(30) A pharmaceutical composition according to (3), comprising (i) about1 to about 20 parts by weight of the low-substitutedhydroxypropylcellulose, whose hydroxypropoxy content is about 7.0 toabout 13.0%, (ii) about 1 to about 20 parts by weight of the acrylicpolymer or salt thereof, whose molecular weight is about 20×10⁴ to about600×10⁴, (iii) about 40 to about 90 parts by weight of the behenic acidhexa(tetra)glyceride and/or tetraglycerol polyricinolate, and (iv) about5 to about 40 parts by weight of indolmycin.

DETAILED DESCRIPTION

The gastrointestinal mucosa-adhesive composition according to thepresent invention is, for instance, a composition comprising an activeingredient having such as anti-HP activity (for example, anantimicrobial substance or an urease inhibitor) and a material whichswells a viscogenic agent (e.g. either a curdlan or a low-substitutedhydroxypropylcellulose or both). The composition is at least adapted toattach itself to the gastrointestinal mucosa (at least gastric mucosa)and/or otherwise stay in the gastrointestine (at least stomach) andrelease the active ingredient such as anti-HP substance containedtherein at a suitable rate and thereby display a potentiatedpharmaceutical effect (e.g. anti-HP action).

An example of the above-mentioned composition would be a compositioncomprising (a) an anti-HP substance as a typical active ingredient and(d) a viscogenic agent capable of being viscous with water (hereinaftersometimes referred to as a viscogenic agent) and also (b) a curdlanand/or a low-substituted hydroxypropylcellulose as a swelling materialand preferably be a composition further comprising (c) a polyglycerolfatty acid ester and/or a lipid. Though there is no particularlimitation on its dosage form, the composition is preferably a solidcomposition and particularly a composition containing a matrix. Thematrix may, for example, be a gastrointestinal mucosa-adhesive matrixcomprising (c) a polyglycerol fatty acid ester and (d) a viscogenicagent in addition to (a) and (b) or a gastrointestinal mucosa-adhesivematrix comprising (c) a lipid and (d) a viscogenic agent in addition to(a) and (b). The preferred matrix is a gastrointestinal mucosa-adhesivematrix comprising (c) a polyglycerol fatty acid ester and (d) aviscogenic agent.

The gastrointestinal mucosa-adhesive matrix comprising said fourcomponents (a), (b), (c), and (d) is preferably a matrix such that theviscogenic agent is dispersed in the matrix which comprises thepolyglycerol fatty acid ester or lipid or a matrix which is covered withthe viscogenic agent. The melting point of the gastrointestinalmucosa-adhesive matrix may, for example, be about 30° to about 120° C.and preferably about 40° to about 120° C.

The polyglycerol fatty acid ester for use in the present invention isesters of polyglycerols with fatty acids and may be a mono- to polyester(diester, triester, etc.). The polyglycerol fatty acid ester ischaracterized in that it does not undergo polymorphic transition or anymaterial interaction with the active ingredient, allowing thosecoexisting ingredients to remain undeactivated and stable for anextended period of time.

Polyglycerol by definition is “a polyhydric alcohol containing n (cyclicform,) to (n+2) (straight-chain form or branched form) hydroxyl groupsand (n−1) (straight-chain form or branched form) to n (cyclic) etherbonds per molecule” [Polyglycerin Esters, (ed.) Sakamoto Yakuhin KogyoCo., Ltd., published Oct. 4, 1994), and any straight-chain ester orbranched-chain ester can be used in the present invention.

For example, compounds of the following formula (I) can be employed.

(wherein n represents a degree of polymerization which is an integer ofnot less than 2). The value of n is generally about 2 to about 50,preferably about 2 to about 20, and for still better results, about 2 toabout 10.

The polyglycerol includes but is not limited to diglycerol, triglycerol,tetraglycerol, pentaglycerol, hexaglycerol, heptaglycerol, octaglycerol,nonaglycerol, decaglycerol, pentadecaglycerol, eicosaglycerol, andtriacontaglycerol. Among those polyglycerols, tetraglycerol,hexaglycerol or decaglycerol is used in many cases.

The fatty acid includes but is not limited to saturated or unsaturatedfatty acids each containing about 8 to about 40, preferably about 12 toabout 25, and more preferably about 15 to about 22 carbon atoms. Thepreferred fatty acid is stearic acid, oleic acid, lauric acid, linoleicacid, linolenic acid, ricinoleic acid, caprylic acid, capric acid, orbehenic acid.

The polyglycerol fatty acid ester includes but is not limited to behenicacid hexa(tetra)glyceride, caprylic acid mono(deca)glyceride, caprylicacid di(tri)glyceride, capric acid di(tri)glyceride, lauric acidmono(tetra)glyceride, lauric acid mono (hexa)glyceride, lauric acidmono(deca)glyceride, oleic acid mono(tetra)glyceride, oleic acidmono(hexa)glyceride, oleic acid mono(deca)glyceride, oleic aciddi(tri)glyceride, oleic acid di(tetra)glyceride, oleic acidsesqui(deca)glyceride, oleic acid penta(tetra)glyceride, oleic acidpenta(hexa)glyceride, oleic acid deca(deca)glyceride, linoleic acidmono(hepta)glyceride, linoleic acid di(tri)glyceride, linoleic aciddi(tetra) glyceride, linoleic acid di(hexa)glyceride, stearic acidmono(di)glyceride, stearic acid mono(tetra)glyceride, stearic acidpenta(tetra)glyceride, stearic acid mono(deca)glyceride, stearic acidtri(tetra)glyceride, stearic acid penta(hexa) glyceride, stearic acidtri(hexa)glyceride, stearic acid deca(deca) glyceride, palmitic acidmono(tetra)glyceride, palmitic acid mono(hexa)glyceride, palmitic acidmono(deca)glyceride, palmitic acid tri(tetra)glyceride, palmitic acidtri(hexa)glyceride, palmitic acid sesqui(hexa)glyceride, palmitic acidpenta(tetra)glyceride, palmitic acid penta(hexa)glyceride, palmitic aciddeca(deca)glyceride, and polyglycerol polyricinolate (e.g. tetraglycerolpolyricinolate, etc.).

The preferred polyglycerol fatty acid ester includes, for instance,behenic acid hexa(tetra)glyceride (e.g. HB-310™, Sakamoto Yakuhin KogyoCo., Ltd.,; Poem J-46B™, Riken Vitamin Co.), stearic acidpenta(tetra)glyceride (e.g. PS-310™, Sakamoto Yakuhin Kogyo Co., Ltd.),stearic acid mono(tetra)glyceride (e.g. MS-310™, Sakamoto Yakuhin KogyoCo., Ltd.), stearic acid penta(hexa)glyceride (e.g. PS-500™, SakamotoYakuhin Kogyo Co., Ltd.), stearic acid mono(deca)glyceride, polyglycerolpolyricinolate (e.g. tetraglycerol polyricinolate, etc.) (e.g. CRS-75™,Sakamoto Yakuhin Co., Ltd.) and mixtures of such glycerides.

Those polyglycerol fatty acid esters can be used each alone or as amixture of two or more species, preferably about 2 or about 3 species.

The molecular weight of the polyglycerol fatty acid ester is generallyabout 200 to about 5000, preferably about 300 to about 3000, preferablyabout 2000 to about 3000. The hydrophile-lipophile balance (HLB) numberof the polyglycerol fatty acid ester is generally about 1 to about 22,preferably about 1 to about 15, more preferably about 1 to about 9, forstill better results, about 1 to about 4. Two or more polyglycerol fattyacid esters differing in HLB number from each other may be used incombination to provide for the designed HLB number. By adjusting the HLBof the polyglycerol fatty acid ester judiciously, the release anddissolution kinetics of the active drug substance can be controlled asdesired.

The proper polyglycerol fatty acid ester can be selected with referenceto the particular active ingredient (e.g. anti-HP agent, etc.),viscogenic agent, swelling material (e.g. curdlan, and/orlow-substituted hydroxypropylcellulose, etc.), the particularcombination thereof, and the objective form of the composition.Preferably, however, compounds which are solid at atmospherictemperature (ca 15° C.) are employed. The melting point of thepolyglycerol fatty acid ester may, for example, be about 15 to about 80°C., preferably about 30 to about 75° C., and for still better results,about 45 to about 75° C.

A suitable polyglycerol fatty acid ester is selected according to thespecies of active ingredient used and the intended dosage form.Generally, polyglycerols with degrees of polymerization in the range ofabout 2 to about 16 are preferred. The particularly preferred range isabout 2 to about 10. Preferred are esters such that the fatty acid hasformed an ester bond with at least one of the (degree of polymerization+2) hydroxyl groups, preferably such that the fatty acid or acids haveformed ester bonds with not less than about 60%, more preferably notless than about 80%, of the total number of hydroxyl groups in thepolyglycerol. The fatty acid or acids are preferably saturated acidseach containing about 6 to about 22, more preferably about 15 to about25, and for still better result, about 18 to about 22 carbon, atoms. Thefatty acid involved in the formation of the ester bonds may be of thesame kind or different kinds.

In the production of a solid composition according to the presentinvention by using two or more different polyglycerol fatty acid estersas a mixture, a liquid polyglycerin fatty acid ester may be included inthe mixture as long as the final composition is solid at atmospherictemperature.

When the polyglycerol fatty acid ester is used as a gastrointestinalmucosa-adhesive matrix, the amount of the polyglycerol fatty acid esterrelative to the total weight of the composition is generally about 5 toabout 98 weight %, preferably about 20 to about 95%, more preferablyabout 40 to about 95% and to the active ingredient in the compositionmay, for example, be about 0.01 to about 15000 times by weight,preferably about 0.1 to about 1000 times by weight, and for still betterresult, about 0.1 to about 100 times by weight.

The lipid for use in the present invention is one having a melting pointof about 40 to about 120° C., preferably about 40 to about 90° C.

The lipid includes but is not limited to saturated fatty acids of about14 to about 22 carbon atoms (e.g. myristic acid, stearic acid, palmiticacid, behenic acid, etc.) or salts (sodium salt, potassium salt, etc.)thereof; higher alcohols of about 16 to about 22 carbon atoms (e.g.cetyl alcohol, stearyl alcohol, etc.); fatty acid glycerol esters suchas the monoglycerides, diglycerides, triglycerides, etc. of theabove-mentioned fatty acids (e.g. 1-monostearate, 1-monopalmitin, etc.);oils (e.g. castor oil, cottonseed oil, beef tallow, etc., inclusive ofthe corresponding hydrogenated oils); waxes (e.g. beeswax, carnauba wax,sperm wax, etc.); hydrocarbons (e.g. paraffin, microcrystalline wax,etc.); and phospholipids (e.g. hydrogenated lecithin etc.). Among thoselipids, oils, waxes, C₁₄₋₂₂ saturated fatty acids, C₁₆₋₂₂ higheralcohols, and hydrocarbons are preferred. The more preferred arehydrogenated cottonseed oil, hydrogenated castor oil, hydrogenatedsoybean oil, carnauba wax, stearic acid, stearyl alcohol, andmicrocrystalline wax. The most preferred is hydrogenated castor oil orcarnauba wax.

When a lipid is used as the gastrointestinal mucosa-adhesive matrix, theamount of the lipid relative to the total weight of the composition isgenerally about 5 to about 98 weight %, preferably about 20 to about 95weight %, more preferably about 40 to about 95 weight %, and to theactive ingredient in the composition is about 0.01 to about 15000 timesby weight, preferably about 0.1 to about 1000 times by weight, and forstill better result, about 0.1 to about 100 times by weight.

The above-mentioned polyglycerol fatty acid ester and lipid may be usedas a mixture. For example, the combination of a polyglycerol fatty acidester with a wax or the combination of a polyglycerol fatty acid esterwith a hydrogenated oil can be mentioned. Specifically, a mixture of 2,3 or more members selected from among behenic acid hexa(tetra)glyceride,stearic acid penta(tetra)glyceride, stearic acid penta(hexa)glyceride,polyglycerol polyricinolate (e.g. tetraglycerol polyricinolate, etc.),carnauba wax, hydrogenated castor oil, and microcrystalline wax, can bementioned.

When the gastrointestinal mucosa-adhesive matrix comprising a viscogenicagent in addition to said polyglycerol fatty acid ester and/or lipid isused for the composition of the invention, the total amount of thepolyglycerol fatty acid ester and lipid relative to the total weight ofthe composition is generally about 5 to about 98 weight %, preferablyabout 20 to about 95 weight %, more preferably about 40 to about 95weight %, and to the active ingredient in the composition is about 0.01to about 15000 times by weight, preferably about 0.1 to about 1000 timesby weight, and for still better result, about 0.1 to about 100 times byweight.

A lipid may be incorporated in a matrix comprising the polyglycerolfatty acid ester. The lipid is a pharmaceutically acceptablewater-insoluble substance capable of regulating the dissolution kineticsof the active ingredient. The lipid includes those species mentionedhereinbefore.

When a lipid and a polyglycerol fatty acid ester are used incombination, the amounts of the lipid and polyglycerol fatty acid needonly be within the range not detracting from the adhesion to thegastrointestinal mucosa and can be selected from said range of totalamount, and the amount of the lipid relative to the polyglycerol fattyacid ester may be about 0.01 to about 1000 times by weight, preferablyabout 0.1 to about 200 times by weight, and for still better results,about 0.1 to about 100 times by weight.

The active ingredient for use in the present invention may be absorbedfrom gastrointestinal mucosa or express its efficacy directly orindirectly in the gastrointestine, such as any anti-HP substance showingactivity against strains of microorganism belonging to the genusHelicobacter (particularly Helicobacter pylori) whether directly orindirectly, thus including antimicrobial substance and inhibitors ofurease which is known to be indispensable for survival of bacteria ofthe genus Helicobacter.

The antimicrobial substance includes but is not limited to antibioticsin the penicillin series (e.g. amoxicillin, benzylpenicillin,piperacillin, mecillinam, etc.), antibiotics in the cephalosporinseries, macrolide antibiotics (e.g. erythromycin, clarithromycin,roxithromycin, azithromycin, etc.), tetracyclines (e.g. tetracycline,minocycline, etc.), aminoglycosides (e.g. gentamicin, amikacin,streptomycin, etc.), bismuth salts (e.g. bismuth acetate, bismuthcitrate, bismuth salicylate, etc.), imidazoles (e.g. metronidazole,tinidazole, miconazole, etc.), quinolones (e.g. ofloxacin,ciprofloxacin, etc.), and tryptophanyl-t-RNA synthesis inhibitors (e.g.oxazolone derivatives (Preferably indolmycin) etc.). Particularlypreferred are penicillins, macrolides, imidazoles, andtryptophanyl-t-RNA synthesis inhibitors. In particular a substance, suchas amoxicillin, clarithromycin or indolmycin is preferred.

The urease inhibitor includes but is not limited to hydroxamic acidderivatives (e.g. acetohydroxamic acid and the compounds described orreferred to in the above-mentioned Synopsis of Lectures at the 4thAnnual Meeting of Medical Chemistry Group), phosphoramide derivatives[e.g. flurofamide (Micro. Ecol. Health Dis. referred to hereinbefore)and phenylphosphorodiamidate compound A (compound of Reference Example2)], phosphates, thiols (e.g. 2-mercaptoethanol etc.), boric acid,halogen compounds (e.g. fluorides etc.), and cassia bark extract (theabove-mentioned Synopsis of Lectures at the 117th Congress ofPharmaceutical Society of Japan).

The swelling material used in the present invention is a material whichswells a viscogenic agent or accelerates the swell of a viscogenic agentcaused by water.

Any type of swelling material can be used in the present invention aslong as it has the characteristics described above and ispharmaceutically acceptable. For instance, preferably a curdlan and/or alow-substituted hydroxypropylcellulose can be used.

The amount of the swelling material in the gastrointestinalmucosa-adhesive composition of the present invention is about 0.5 toabout 50 weight %, preferably about 1 to about 40 weight %, and forstill better results, about 1 to about 30 weight %, relative to thetotal weight of the composition.

The curdlan for use in the present invention is a linear water-insolublepolysaccharide (β-1,3-glucan) produced by microorganisms (such asAlcaligenes faecalis var. myxogenes etc.), which includes such speciesas curdlan 10C3K, 13140, 12607, 12665, 13127, 13256, 13259, and 13660[New Food Industry, 20, No. 10, p. 49 (1978)]. Among those and otherspecies of curdlan, those which are acceptable as pharmaceutical basesor excipients can be employed. A preferred example is curdlan N (a foodadditive).

The amount of the curdlan in the gastrointestinal mucosa-adhesivecomposition of the invention relative to the total weight of thecomposition is about 0.5 to about 50 weight %, preferably about 1 toabout 40 weight %, and more preferably about 1 to about 30 weight %.

The low-substituted hydroxypropylcellulose for use in the presentinvention is a cellulose derivative available upon substitution ofhydroxypropoxy for some of the hydroxy groups of cellulose, which has ahydroxypropoxy content of 5.0 to 16.0% (as specified in the JapanesePharmacopoeia Twelfth Edition). The low-substituted hydroxypropylcellulose mentioned above is useful, in particular, one which has ahydroxypropoxy content of 7.0 to 13.0% (e.g. L-HPC™, Shin-EtsuChemicals., Co., Ltd. is preferred. Thus, those derivatives with adegree of substitution within the above range and varying in particlediameter, such as LH-11™ (Shin-Etsu Chemicals., Co., Ltd.)hydroxypropoxy content 10.0 to 12.9%, particle size distribution ≧98%under 150 μm sieve and ≦0.5% on 180 μm sieve), LH-20™ (hydroxypropoxycontent 13.0-16.0%, particle size distribution >90% under 75 μm sieveand ≦1.0% on 106 μm sieve), LH-21 (Shin-Etsu Chemicals., Co., Ltd.,hydroxypropoxy content 10.0 to 12.9%, particle size distribution ≧90%under 75 μm sieve and ≦1.0% on 106 μm sieve), LH-22 (Shin-EtsuChemicals., Co., Ltd., hydroxypropoxy content 7.0 to 9.9%, particle sizedistribution ≧90% under 75 μm sieve and ≦1.0% on 106 μm sieve), andLH-31 (Shin-Etsu Chemicals., Co., Ltd., hydroxypropoxy content 10.0 to12.9%, mean particle diameter not greater than 30 μm, particle sizedistribution ≧50% under 45 μm sieve and ≦5.0% on 75 μm sieve), amongothers, can be utilized.

Preferably, LH-22 or LH-31 are utilized.

The amount of the low-substituted hydroxypropylcellulose in thegastrointestinal mucosa-adherent composition of the present invention isabout 0.5 to about 50 weight %, preferably about 1 to about 40 weight %,and for still better results, about 1 to about 30 weight %, relative tothe total weight of the composition.

Any type of viscogenic agent can be used in the present invention aslong as it becomes sufficiently viscous with water to attach itself tothe gastrointestinal mucosa and is pharmaceutically acceptable.Preferred, however, are those substances which are markedly swollen bywater and develop high degrees of viscosity. The viscogenic agent, thus,includes synthetic polymers and naturally-occurring viscogenicmaterials.

The preferred synthetic polymer is a polymer such that the viscosity ofa 2% aqueous solution thereof at 20° C. is about 3 to about 50000 cps.,preferably about 10 to about 30000 cps., and for still better results,about 15 to about 30000 cps. However, when a basic or an acidic polymerwhich gains in viscosity on neutralization is used, the preferredpolymer is such that the viscosity of a 0.2% solution thereof afterneutralization at 20° C. is about 100 to about 500000 cps, preferablyabout 100 to about 200000 cps, and for still better results, about 1500to about 100000 cps.

The value of the viscosity is measured with a Brookfield viscometer.

Preferably the above-mentioned polymer is an acidic polymer whichincludes but is not limited to carboxyl- or sulfo-containing polymersand the corresponding salt-containing polymers. Particularly preferredare carboxyl-containing polymers and carboxylate salt-containingpolymers.

The carboxyl (inclusive of its salt)-containing polymer is preferably anacrylic homopolymer or copolymer containing acrylic acid as a monomerunit or a salt thereof. The salt includes monovalent metal salts such asthe sodium salt, potassium salt, etc. and divalent metal salts such asthe magnesium salt, calcium salt, ammonium salt, etc.

The acrylic polymer, inclusive of its salt, includes polymers containingcarboxyl groups in a proportion of about 58 to about 63 weight % andhaving a molecular weight of about 20×10⁴ to about 600×10⁴, preferablyabout 100×10⁴ to about 600×10⁴, and more preferably about 100×10⁴ toabout 500×10⁴. The preferred acrylic polymer, inclusive of its salt,includes acrylic acid homopolymers and their salts. Such polymers arelisted under the heading of carboxyvinyl polymer in Japanese Standardsof Pharmaceutical Ingredients (October 1986).

As specific examples of said acrylic polymer, there can be mentionedcarbomer [Carbopol™ (hereinafter referred to as Carbopol), The B. F.Goodrich Company] 940, 934, 934P, 941, 1342, 974P, 971P (NF XVIII),EX214 etc., HIVISWAKO™ 103, 104, 105, and 204 (Wako Pure ChemicalIndustries), NOVEON AA1™ (The B. F. Goodrich Company), and calciumpolycarbophil (USP XXIII)).

The naturally-occurring viscogenic agent includes but is not limited tomucin, agar, gelatin, pectin, carrageenin, sodium alginate, locust beangum, xanthan gum, tragacanth gum, chitosan, pullulan, waxy starch,sucralfate, curdlan, and cellulose and its derivatives (cellulosesulfate and preferably hydroxypropylcellulose orhydroxypropylmethylcellulose).

The most preferred viscogenic agent is an acrylic polymer or its salt.

Those viscogenic agents can be used alone or in combination.

Referring to the amount of the viscogenic agent for use in thecomposition of the invention, its amount in the gastrointestinalmucosa-adherent matrix may for example be about 0.005 to about 99 weight%, preferably about 0.5 to about 45 weight %, more preferably about 1 toabout 30 weight %, furthermore preferably about 1 to about 25 weight %,and for still better result, about 1 to about 20 weight %. When, forexample, the viscogenic agent is dispersed in a matrix comprising thepolyglycerol fatty acid ester and/or lipid, the amount of the viscogenicagent is about 0.005 to about 95 weight %, preferably about 0.5 to about30 weight %, and more preferably about 1 to about 25 weight %, and forstill better result, about 1 to about 20 weight % based on the totalweight. When the matrix is coated with the viscogenic agent, theproportion of the viscogenic agent is also about 0.005 to about 95weight %, preferably about 0.5 to about 30 weight %, and more preferablyabout 1 to about 25 weight %, and for still better result, about 1 toabout 20 weight % based on the total weight.

When the composition of the present invention contains a curdlan as aswelling material, the composition is capable of attaching itself to thegastrointestinal mucosa even without addition of said viscogenic agent,for the curdlan acts as a viscogenic agent by itself. In this case, thecurdlan may be formulated in an amount beyond the range definedhereinbefore for imparting the necessary adherent effect.

The gastrointestinal mucosa-adherent composition comprising theviscogenic agent dispersed in a matrix comprising a polyglycerol fattyacid ester and/or lipid may be any dispersion of the polyglycerol fattyacid ester and/or lipid, viscogenic agent, curdlan and/orlow-substituted hydroxypropylcellulose, and active ingredient.Dispersion can be effected by the analogue to the per se knowntechnology.

The technology for production of a gastrointestinal mucosa-adherentcomposition is now described.

1) The gastrointestinal mucosa-adherent composition, which is solid atatomospheric temperature, can be produced in a similar manner to the perse known technology. A typical process comprises melting thepolyglycerol fatty acid ester and/or lipid at a temperature beyond itsmelting points adding said viscogenic agent, anti-HP agent, and curdlanand/or low-substituted hydroxypropylcellulose either at one time orserially to the melt to thereby disperse them in the melt, and coolingthe dispersion. The heating temperature may for example be about 40 toabout 150° C., preferably about 50 to about 110° C., and more preferablyabout 50 to about 100° C. This process can be carried out with aconventional granulating machine and the composition is preferablymolded into solid beads (e.g. granules, finegranules, etc.) by spraycooling, for example spray chilling.

The spray chilling method may typically comprise dripping a mixeddispersion of the viscogenic agent, curdlan and/or low-substitutedhydroxypropylcellulose, and active ingredient in a molten polyglycerolfatty acid ester and/or lipid at a constant flow rate onto a rotary diskrevolving at a high speed of, for example, about 10 to about 6000 rpm,preferably about 900 to about 6000 rpm, and more preferably about 1000to about 5000 rpm. The rotary disk may for example be a flat, smoothdisk, typically made of aluminum and measuring about 5 to about 100 cmin diameter, preferably about 10 to about 20 cm in diameter. Thedripping rate of said molten dispersion can be selected according to thedesigned particle diameter and is generally about 1 to about 1000g/min., preferably about 2 to about 200 g/min., more preferably about 5to about 100 g/min. The granules thus obtained are true to spheres sothat a uniform film can be formed on their surface with good efficiencyin the subsequent coating step.

An alternative production process comprises kneading the viscogenicagent, curdlan and/or low-substituted hydroxypropylcellulose, and activeingredient into the polyglycerol fatty acid ester and/or lipid andgranulating the resulting dispersion. The solvent for use in thisprocess may be a solvent of the common variety (e.g. methanol,acetonitrile, chloroform, etc.).

A further alternative process for producing the solid compositioncomprises the use of the melt granulation technology. A typical meltgranulation process comprises heating the polyglycerol fatty acid-esterand/or lipid at a temperature near its melting point, for example, atemperature from its melting point to a temperature about 5° C. belowthe melting point, subjecting the resulting melt to granulation, such asthe above-mentioned spray chilling, and suspending the resulting fineparticles together with the viscogenic agent, anti-HP agent, and curdlanand/or low-substituted hydroxypropylcellulose under heating at asuitable temperature to provide an adherent matrix-drug system., In thiscase, the influence of heat on the active ingredient can be avoided.Therefore, even when the active ingredient is a peptide or a protein, asolid composition can be manufactured without deactivating of the activesubstance.

The solid composition comprising a matrix made up of a polyglycerolfatty acid ester and/or a lipid and coated with a viscogenic agent maybe a preparation coated with such a viscogenic agent alone or a mixtureof a viscogenic agent and a swelling material (e.g. curdlan and/or alow-substituted hydroxypropylcellulose etc), preferably with a coatingmaterial containing either a viscogenic agent alone or a viscogenicagent plus a curdlan and/or a low-substituted hydroxypropylcellulose.The coating material may be a composition containing at least one memberselected from among said polyglycerol fatty acid ester, said lipid, andsaid water-insoluble polymer. When a viscogenic agent which is sparinglycompatible or incompatible with the components of the solid compositionis employed for coating, the solid composition can be provided with afilm in which the viscogenic agent has been dispersed. The coatingmaterial may further contain the additives mentioned hereinbefore.

The water-insoluble (hydrophobic) polymer includes but is not limited tohydroxypropylmethylcellulose phthalate (The Japanese PharmacopoeiaTwelfth Edition), hydroxypropylmethylcellulose acetate succinate(Shin-Etsu Chemicals Co., Ltd.), carboxymethylethylcellulose (FreundIndustries Co., Ltd., CMEC, Japanese Standards of PharmaceuticalIngredients, 1986), cellulose acetate trimellitate (Eastman), celluloseacetate phthalate (The Japanese Pharmacopoeia Twelfth Edition),ethylcellulose (Asahi Chemical Industry Co., Ltd.), aminoalkylmethacrylate copolymer (Röhm-Pharma, Eudragit™ RS-100, RL-100, RL-PO,RS-PO, RS-30D, RL-30D), methacrylic acid-ethyl acrylate copolymer(Röhm-Pharma, Eudragit™ L100-55), methacrylic acid-methyl methacrylatecopolymer (Röhm-Pharma, Eudragit™ L-100, S-100), Eudragit™ 30D-55,Eudragit™ NE-30D (Röhm-Pharma), and polyvinyl acetate (Colorcon). Thosehydrophobic polymers can be used independently or as a mixture of two ormore different polymers.

The proportion of the viscogenic agent in the coating material is about0.005 to about 100 weight %, preferably about 0.05 to about 95 weight %,more preferably about 0.05 to about 30 weight %, and for still betterresult, about 1 to about 10 weight % based on the whole solid fractionof the coating material.

When at least one of the polyglycerol fatty acid ester, lipid, andhydrophobic polymer is used in combination with the viscogenic agent forthe coating material, the proportion of the viscogenic agent based onthe total weight of the solid fraction of the coating material is about0.05 to about 95 weight %, preferably about 0.5 to about 95 weight %,more preferably about 0.5 to about 30 weight %, futhermore preferablyabout 5 to about 30 weight %, and for still better result, about 5 toabout 25 weight %.

Referring further to the coating material, two or more members selectedfrom the class consisting of the polyglycerol fatty acid ester, lipid,and hydrophobic polymer can be used in combination. In this case, basedon each part by weight of the whole polyglycerol fatty acid ester and/orlipid, the remaining component is used in a proportion of about 0.0001to about 1000 part by weight, preferably about 0.01 to about 100 part byweight, and more preferably about 0.01 to about 10 part by weight.

The coating amount can be selected according to the type of solidcomposition and the desired strength of adhesion to the mucosa. Forexample, the coating amount for a solid composition may be about 0.1 toabout 30 weight %, preferably about 0.5 to about 20 weight %, fortablets and about 0.1 to about 100 weight %, preferably about 1 to about50 weight %, for fine granules.

Where necessary, the coating material may be supplemented with thecommon additives such as those mentioned hereinbefore. For example, thecoating material and the additive may be added together or separately,etc. applied. The proportion of the additive relative to the solidfraction of the coating material is about 0.1 to about 70 weight %,preferably about 1 to about 50 weight %, and more preferably about 20 toabout 50 weight %.

The coating technology that can be used includes a variety of per seknown methods, such as pan coating, fluidized-bed coating, roll coating,and so on. When the coating material is a solution or dispersioncontaining water or an organic solvent, the spray coating method canalso be employed. There is no particular limitation on the kind of saidwater or organic solvent. Thus, for example, alcohols such as methanol,ethanol, isopropyl alcohol, etc.; ketones such as acetone etc.; andhalogenated hydrocarbons such as chloroform, dichloromethane,trichloromethane, etc. can be used.

When the polyglycerol fatty acid ester and/or lipid is used for coating,the objective coated composition can be produced by melting thepolyglycerol fatty acid ester and/or lipid, optionally together withother additives, under heating, emulsifying the melt with water,spray-coating the surface of a solid composition with the resultingemulsion, and drying the coat. An alternative procedure comprises addingthe coating material to the solid composition preheated in a coating panor the like and melt-spreading the coating.

The solid composition is coated generally at a temperature of about 25to about 60° C. and preferably at about 25 to about 40° C.

The coating time can be judiciously selected with reference to thecoating method, the characteristics and amount of the coating material,and characteristics of the substrate solid composition.

Insofar as a sufficient adhesion to the gastrointestinal mucosa can beassured, the gastrointestinal mucosa-adherent solid composition may, ifnecessary, be further coated with a conventional gastric coating agentor a water-soluble coating agent.

The gastrointestinal mucosa-adherent composition according to thepresent invention can generally be administered orally as it is or in asuitable preparation. The solid oral dosage form includes but is notlimited to fine granules, granules, pills, tablets manufactured bycompressing said fine granules or granules with a tablet machine, andcapsules manufactured by filling said fine granules or granules intosuitable capsule shells. Among those preparations, fine granules andgranules are preferred.

The particle size distribution of said fine granules may for example be:particles measuring about 10 to about 500 μm in diameter accounting fornot less than about 75 weight %, particles larger than about 500 μmaccounting for not more than about 5 weight %, and particles smallerthan about 10 μm accounting for not more than about 10 weight %. Thepreferred distribution is about 105 to about 500 μm accounting for about≧75 weight %, about ≧500 μm accounting for not more than about 5 weight%, and about ≦74 μm accounting for not more than about 10 weight %. Theparticle size distribution of said granules may for example be about 500to about 1410 μm accounting for not less than about 90 weight % andabout ≦177 μm accounting for not more than about 5 weight %.

2). When the gastrointestinal mucosa-adherent composition is to beprovided as a liquid composition, such a liquid composition can bemanufactured by the manner similar to the per se known technology. Atypical procedure comprises mixing a polyglycerol fatty acid esterand/or a lipid, which is liquid at atmospheric temperature, a viscogenicagent, a active ingredient, and a swelling material (e.g. a curdlanand/or a low-substituted hydroxypropylcellulose etc.) all at once orserially to provide a dispersion or solution.

The dosage form comprising such a liquid adherent mucosal medicationsystem includes but is not limited to syrups, emulsions, suspensions,and encapsulated versions thereof.

The proportion of the active ingredient (e.g. an anti-HP agent etc.) inthe composition of the invention is about 0.005 to about 95 weight %,preferably about 1 to about 95 weight %, and more preferably about 10 toabout 95 weight %, and for still better result, about 10 to about 50.

The composition of the present invention is relatively non-toxic, andeffective, for instance, in the treatment of Helicobacterpylori-harboring mammals (e.g. feline, bovine, canine, equine, goat,monkey, human, etc.). The composition exhibits marked efficacy in theclearance and extermination of Helicobacter pylori in such animals.Therefore the composition is useful for the prophylaxis, treatment, andprevention of relapse of Helicobacter pylori related gastrointestinaldisease. The indication includes but is not limited to gastritis andgastrointestinal ulcer, and stomach cancer, and a particularlyremarkable response can be obtained in the treatment of gastrointestinalulcer.

The gastrointestinal mucosa-adherent composition of the presentinvention can be administered, generally by the oral route, to mammalsincluding humans. If desired, the composition may be compounded orformulated with pharmacologically and pharmaceutically acceptableadditives (e.g. diluent, excipient, binder, disintegrator, coloringagent, stabilizer, etc.) just as mentioned hereinbefore.

The preparations containing the gastrointestinal mucosa-adherentcomposition may be further supplemented with other pharmacologicallyactive ingredients, such as antimicrobials, antiulcerative agents,antacids, gastric acid antisecretory agents, analgesics, and nutrients(vitamins etc.), unless the pharmacologic activities of the respectiveingredients are compromised by mutual interference.

The antibacterials mentioned above include but are not limited tomacrolides (e.g. clarithromycin, roxithromycin, azithromycin, etc.),quinolones (e.g. tarivid, ozex, pefloxacin, etc.), penicillins (e.g.furopenem etc.), and cephalosporins (e.g. flumax etc.).

The antiulcerative agent includes but is not limited to therapeuticdrugs for gastrointestinal ulcer, such as proton pump inhibitors, H₂blockers, and mucosal protectant antiulceratives.

The proton pump inhibitor includes benzimidazole compounds havingantiulcerative activity, particularly 2-[(pyridyl)-methylsulfinyl ormethylthio]benzimidazole derivatives and their salts. Specifically,2-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methylsulfinyl]-1H-benzimidazole(lansoprazole), 2-[(2-pyridinylmethyl)sulfinyl]-1H-benzimidazole(timoprazole),5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole(omeprazole),2-[2-[4-(3-methoxypropoxy)-3-methylpyridyl]methylsulfinyl]-1H-benzimidazolesodium,5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole(pantoprazole), etc. can be mentioned. The above benzimidazole compoundsand salts can be produced by the processes described in, inter alia,Japanese Patent Unexamined Publication NO.141783/1979, Patent UnexaminedPublication NO.192880/1983, Patent Unexamined Publication NO.50978/1986,Patent Unexamined Publication NO.116576/1987 and Patent UnexaminedPublication NO.59043/1993 or any production processes analogous thereto.Aside from the above compounds,2-[[o-(isobutylamino)benzyl]sulfinyl]benzimidazole (leminoprazole) and2-[4-methoxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine can also bementioned.

The H₂ blocker includes but is not limited to2-cyano-1-methyl-3-[2-[[(5-methylimidazol-4-yl)methyl]thio]ethyl]guanidine(cimetidine),N-[2-[[[5-[(dimethylamino)methyl]furanyl]thio]ethyl]-N′-methyl-2-nitro-1,1-ethenediamine(ranitidine), and(±)-2-(furfurylsulfinyl)-N-[4-[4-(piperidinylmethyl)-2-pyridyl]oxy(z)-2-butinyl]acetamide(loctidine).

The mucosal protectant antiulcerative includes but is not limited to(z)-7-[(1R,2R,3R)-2-[(E)-(3R)-3-hydroxy-4,4-dimethyl-1-octenyl]-3-methyl-5-oxocyclopentyl]-5-heptenoicacid (trimoprostil, ulstar), 1-butyric acid-7-(L-2-aminobutyricacid-26-L-aspartic acid-27-L-valine-29-L-alanine)calcitonin (elcatonin),and sodium 3-ethyl-7-isopropyl-1-azulenesulfonate (egualen sodium).

When the above composition is processed into a solid preparation, thoseadditives which are conventionally used in the manufacture of solidpharmaceutical preparations (e.g. tablets, fine granules, granules,etc.) can be employed. Among such additives are excipients such as cornstarch, talc, crystalline cellulose (Avicel), powdered sucrose,magnesium stearate, mannitol, light silicic anhydride, magnesiumcarbonate, calcium carbonate, L-cysteine, etc.; binders such as starch,sucrose, gelatin, gum arabic powder, methylcellulose,carboxymethylcellulose, carboxymethylcellulose sodium,hydroxypropylcellulose, hydroxypropylmethylcellulose,polyvinylpyrrolidone, pullulan, dextrin, etc.; disintegrators such ascarboxymethylcellulose calcium, low-substitutedhydroxypropylmethylcellulose, croscarmellose sodium, etc.; anionicsurfactants such as sodium alkyl sulfonates etc. and nonionicsurfactants such as polyoxyethylene sorbitan fatty acid esters,polyoxyethylene fatty acid esters, polyoxyethylated castor oilderivatives, etc.; antacids or mucosal protectants such as magnesiumhydroxide, magnesium aluminosilicate, sucralfate, etc.; coloring agents;corrigents; adsorbents; antiseptics; lubricants; and antistatic agents.The levels of addition of those additives can be selected within therange not detracting from adhesion to the mucosa.

The dosage of the composition of the invention should vary withdifferent dosage forms, administration modalities, and included activeingredient. It is likely that compared with administration of theingredient alone, the dosage of the drug can be reduced to one-halfthrough about one-twentieth when the composition of the invention isused.

When the pharmaceutical composition of the invention is to beadministered orally to a human being for the therapy of Helicobacterpylori infection, taking the case in which the active ingredient is anantimicrobial substance as an example, the daily dose for an adultpatient may be about 0.1 to about 50 mg/kg or preferably about 0.3 toabout 40 mg/kg in terms of the active substance. Taking the case inwhich the active substance is a urease inhibitor as an example, thedaily dose for an adult patient is about 0.05 to about 100 mg/kg orpreferably about 0.2 to about 100 mg/kg, more preferably about 0.2 toabout 20 mg/kg, furthermore preferably about 0.2 to about 10 mg/kg, andfor still better result, about 0.5 to about 10 mg/kg in terms of theactive substance.

Furthermore, the preparation of the invention and an independent dosageform comprising said antiulcerative agent can be administered to thesame recipient either concurrently or at staggered times for thetreatment of gastritis or gastrointestinal ulcer and such a combinationtherapy is useful for the therapy or symptomatic relief of suchdiseases.

MODE OF WORKING THE INVENTION

The following examples and test examples illustrate the presentinvention in further detail, however those examples should by no meansbe construed as limiting the scope of the invention.

Reference Example 1 5-Methyl-2-thiophenecarboxamide

5-Methyl-2-thiophenecarbaldehyde (2.6 g, 0.1 M), hydroxylaminehydrochloride (8.3 g, 0.12 M), and sodium acetate (9.8 g, 0.12 M) wereadded to. acetic acid (50 ml) and the mixture was refluxed for 13 to 15hours. After disappearance of the starting material was confirmed byhigh performance liquid chromatography (HPLC retention time ca 13 min.),the reaction mixture was concentrated under reduced pressure to aboutone-half of its volume. To this concentrate was added concentratedhydrochloric acid (100 ml) and the reaction was allowed to proceed at60° C. for 4 hours. The reaction mixture was then diluted with 100 ml ofwater and stirred under ice-cooling for 30 minutes. The resultingcrystals were recovered by filtration and rinsed with 100 ml of icedwater to provide 5-methyl-2-thiophenecarboxamide (HPLC retention time ca4 min.)

(11.6 g, yield 82%).

HPLC parameter settings

Column: GL Sciences' Inertsil ODS-3, 5 m, 4.6×150 mm

Eluent: acetonitrile: 0.05 M potassium dihydrogen phosphate (aq.sol.)=30:70

Detection wavelength: 231 nm

Flow rate: 1.0 ml/min.

¹H-NMR (DMSO-d₆) d: 2.54 (3H, d, CH₃), 7.01 (1H, dd, thiophen-4-H), 7.78(1H, dd, thiophen-3-H).

Reference Example 2N-(diaminophosphinyl)-5-methyl-2-thiophenecarboxamide

5-Methyl-2-thiophenecarboxamide (7.6 g, 47 mM) was suspended in toluene(50 ml), followed by addition of phosphorus pentachloride (10.9 g, 50mM) with vigorous stirring at room temperature. The mixture was heatedto 65° C. and stirred at that temperature for 30 minutes. Then, undercooling with ice, formic acid (2.0 ml) was added dropwise. The mixturewas stirred at 25° C. for 30 minutes, after which the toluene wasdistilled off under reduced pressure. After the residue was dissolvedtetrahydrofuran (THF, 100 ml), 25% aqueous ammonia (17.1 ml) was addedwith ice-cooling and the mixture was stirred at 25° C. for 30 minutes.Then, toluene (100 ml) was added and the crystals that separated outwere harvested by filtration. This crystal crop was rinsed with THF (50ml) and water (50 ml) and dried in vacuo to provideN-(diaminophosphinyl)-5-methyl-2-thiophenecarboxamide (6.78 g, 64%).m.p. 285-297° C. (decomp.).

EXAMPLE 1

Production of a urease inhibitor-containing gastrointestinalmucosa-adherent preparation

A mixture of hydrogenated caster oil (Lubri wax 101™, Freund IndustrialCo. Ltd.) (63.0 g) and behenic acid hexa (tetra) glyceride (HB-310™,Sakamoto Yakuhin Kogyo Co. Ltd.)(5.0 g) was melted at 84° C. To thismelt, 4.0 g of N-(diaminophosphinyl)-5-methyl-2-thiophenecarboxamide(hereinafter referred to as compound A), 8.0 g of acrylic polymer(HIVISWAKO 104™, Wako Pure Chemical Industries, Ltd.) and 20.0 g ofCurdlan (Takeda Chemical Industries, Ltd.) were serially added and themixture was stirred for dispersion at a constant temperature of 84° C.for 15 minutes. This molten mixture was dropped onto a 15 cm (di.)aluminum disk rotating at 1950 rpm at a flow rate of 10 g/min, wherebyspherical fine granules passing through a 42-mesh sieve but failing topass through a 60-mesh sieve (hereinafter referred to briefly as 42/60mesh) were obtained.

EXAMPLE 2

Production of a urease inhibitor-containing gastrointestinalmucosa-adherent preparation

A mixture of hydrogenated caster oil (Lubri wax 101™, Freund IndustrialCo. Ltd.) (63.0 g) and behenic acid hexa (tetra) glyceride, (HB-310™,Sakamoto Yakuhin Kogyo Co. Ltd.)(5.0 g) was melted at 84° C. To thismelt, 4.0 g of compound A, 8.0 g of acrylic polymer (HIVISWAKO 104™,Wako Pure Chemical Industries, Ltd.) and 20.0 g of low substitutedhydroxypropylcellulose (LH-31™, Shin-Etsu Chemicals) were serially addedand the mixture was stirred for dispersion at a constant temperature of84° C. for 15 minutes. This molten mixture was dropped onto a 15 cm(di.) aluminum disk rotating at 1950 rpm at a flow rate of 10 g/min,whereby 42/60 mesh spherical fine granules were obtained.

EXAMPLE 3

Production of a urease inhibitor-containing gastrointestinalmucosa-adherent preparation

Behenic acid hexa (tetra) glyceride (HB-310™, Sakamoto Yakuhin Kogyo Co.Ltd.)(81.5 g) was melted at 84° C. To this melt, 0.5 g of compound A,8.0 g of acrylic polymer (HIVISWAKO 104™, Wako Pure Chemical Industries,Ltd.) and 10.0 g of Curdlan (Takeda Chemical Industries, Ltd.) wereserially added and the mixture was stirred for dispersion at a constanttemperature of 84° C. for 15 minutes. This molten mixture was droppedonto a 15 cm (di.) aluminum disk rotating at 1950 rpm at a flow rate of10 g/min, whereby 42/60 mesh spherical fine granules were obtained.

EXAMPLE 4

Production of a urease inhibitor-containing gastrointestinalmucosa-adherent preparation

A mixture of hydrogenated caster oil (Lubri wax 101™, Freund IndustrialCo. Ltd.) (54.0 g) and behenic acid hexa (tetra) glyceride (HB-310™,Sakamoto Yakuhin Kogyo Co. Ltd.)(1.0 g) was melted at 84° C. To thismelt, 35.0 g of compound A, 5.0 g of acrylic polymer (HIVISWAKO 104™,Wako Pure Chemical Industries, Ltd.) and 5.0 g of Curdlan (TakedaChemical Industries, Ltd.) were serially added and the mixture wasstirred for dispersion at a constant temperature of 84° C. for 15minutes. This molten mixture was dropped onto a 15 cm (di.) aluminumdisk rotating at 1950 rpm at a flow rate of 10 g/min, whereby 42/60 meshspherical fine granules were obtained.

EXAMPLE 5

Production of a urease inhibitor-containing gastrointestinalmucosa-adherent preparation

A mixture of hydrogenated caster oil (Lubri wax 101™, Freund IndustrialCo. Ltd.) (35.0 g) and behenic acid hexa (tetra) glyceride (HB-310™,Sakamoto Yakuhin Kogyo Co. Ltd.)(1.0 g) was melted at 84° C. To thismelt, 35.0 g of compound A, 5.0 g of acrylic polymer (HIVISWAKO 104™Wako Pure Chemical Industries, Ltd.) and 5.0 g of low substitutedhydroxypropylcellulose (LH-31™, Shin-Etsu Chemicals) were serially addedand the mixture was stirred for dispersion at a constant temperature of84° C. for 15 minutes. This molten mixture was dropped onto a 15 cm(di.) aluminum disk rotating at 1950 rpm at a flow rate of 10 g/min,whereby 42/60 mesh spherical fine granules were obtained.

EXAMPLE 6

Production of a urease inhibitor-containing gastrointestinalmucosa-adherent preparation

A mixture of hydrogenated caster oil (Lubri wax 101™, Freund IndustrialCo. Ltd.) (54.0 g) and behenic acid hexa (tetra) glyceride (HB-310™,Sakamoto Yakuhin Kogyo Co. Ltd.)(1.0 g) was melted at 84° C. To thismelt, 35.0 g of compound A, 5.0 g of acrylic polymer (HIVISWAKO 104™,Wako Pure Chemical,Industries, Ltd.) and 5.0 g of low substitutedhydroxypropylcellulose (LH-31™, Shin-Etsu Chemicals) were serially addedand the mixture was stirred for dispersion at a constant temperature of84° C. for 15 minutes. This molten mixture was dropped onto a 15 cm(di.) aluminum disk rotating at 1950 rpm at a flow rate of 10 g/min,whereby 42/60 mesh spherical fine granules were obtained.

EXAMPLE 7

Production of a urease inhibitor-containing gastrointestinalmucosa-adherent preparation

Hydrogenated caster oil (Lubri wax 101™, Freund Industrial Co. Ltd.)(76.0 g) was melted at 84° C. To this melt, 4.0 g of compound A, 10.0 gof acrylic polymer (HIVISWAKO 104™, Wako Pure Chemical Industries, Ltd.)and 10.0 g of low substituted hydroxypropylcellulose (LH-31™, Shin-EtsuChemicals) were serially added and the mixture was stirred fordispersion at a constant temperature of 84° C. for 15 minutes. Thismolten mixture was dropped onto a 15 cm (di.) aluminum disk rotating at1950 rpm at a flow rate of 10 g/min, whereby 42/60 mesh spherical finegranules were obtained.

Test Example 1

In vivo anti-Helicobacter pylori effect of the compound A-containinggastrointestinal mucosa-adherent preparation

Mice (Crj: ICR) infected with Helicobacter pylori (hereinafter sometimesreferred to briefly as HP) were subcutaneously dosed with a lansoprazole(hereinafter referred to briefly as LPZ)-containing 0.5% methylcellulosesuspension. At 30 minutes after administration, the compoundA-containing gastrointestinal mucosa-adherent preparation obtained inExample 6 (AdMMS in Table 1) or a 1.0% NaHCO3/0.5% methylcellulosesuspension containing compound A (Suspension in Table 1) was orallyadministered twice a day for 3 consecutive days at a dose of 10 mg/kg ascompound A for AdMMS or 100 mg/kg as compound A for the suspension. At16 hours after the final dose, the stomach was excised and the gastricwall was homogenized and serial dilutions were plated on the HPselective medium. The inoculated medium was incubated for 4 days at 37°C. under microaerobic conditions and the number of viable cells wascounted. The results are shown in Table 1.

TABLE 1 Bacterial recovery Log CFU/gastric Dose (mg/kg) wall PreparationCompound-A LPZ Mean ± SE Control 0 0 4.54 ± 0.30 Suspension 100 10 3.14± 0.86 AdMMS 10 10 3.39 ± 1.21

The compound A-containing gastrointestinal mucosa-adherent preparation(AdMMS) showed an equivalent anti-HP effect at the dose of one-tenth ofthe suspension.

EXAMPLE 8

Production of amoxicillin-containing gastrointestinal mucosa-adherentpreparation

Hydrogenated caster oil (Lubri wax 101™, Freund Industrial Co. Ltd.)(75.0 g) was melted at 95° C. To this melt, 1.5 g of amoxicillin(Beecham Pharmaceuticals (PTE) Ltd.) (hereinafter referred to as AMPC),10.0 g of acrylic polymer (HIVISWAKO 104™, Wako Pure ChemicalIndustries, Ltd.) and 13.5 g of Curdlan (Takeda Chemical Industries,Ltd.) were serially added and the mixture was stirred for dispersion ata constant temperature of 95° C. for 15 minutes. This molten mixture wasdropped onto a 15 cm (di.) aluminum disk rotating at 1950 rpm at a flowrate of 10 g/min, whereby 42/60 mesh spherical fine granules wereobtained.

Comparative Example 1

Production of amoxicillin-containing gastrointestinal mucosa-adherentpreparation

Carnauba wax (Polishing wax 103, Freund Industrial Co. Ltd.) (88.5 g)was melted at 95° C. To this melt, 1.5 g of ambxicillin (BeechamPharmaceuticals (PTE) Ltd.) (hereinafter referred to as AMPC) and 10.0 gof acrylic polymer (HIVISWAKO 104™, Wako Pure Chemical Industries, Ltd.)were serially added and the mixture was stirred for dispersion at aconstant temperature of 95° C. for 15 minutes. This molten mixture wasdropped onto a 15 cm (di.) aluminum disk rotating at 1950 rpm at a flowrate of 10 g/min, whereby 42/60 mesh spherical fine granules wereobtained.

Test Example 2

In vivo anti-Helicobacter pylori effect of the AMPC-containinggastrointestinal mucosa-adherent preparation

Mongolian gerbils (MGS/Sea) infected with HP were orally dosed with theAMPC-containing gastrointestinal mucosa-adherent preparation obtained inExample 8 (AMPC-AdMMS-8 in Table 2), the AMPC-containinggastrointestinal mucosa-adherent preparation obtained in ComparativeExample 1 (AMPC-AdMMS-C1 in Table 2), and a 0.5% methylcellulosesuspension containing AMPC (AMPC suspension in Table 2), respectively ata dose of 10 mg/kg as AMPC twice a day for 3 consecutive days. At 16hours after the final dose, the stomach was excised and the gastric wallwas homogenized and serial dilutions were plated on the HP selectivemedium. The inoculated medium was incubated for 4 days at 37° C. undermicroaerobic conditions and the number of viable cells was counted. Theresults are shown in Table 2.

TABLE 2 Bacterial recovery Clearance Log Dose rate CFU/gastric (mg/kg)Cleared/tota wall Formulation AMPC l (%) Mean ± SE Control 0 0/5 (0)7.02 ± 0.33 AMPC- 10 1/5 (20) 3.12 ± 1.45 suspension AMPC-AdMMS-8 10 5/5(100) ND AMPC-AdMMS-C1 10 2/5 (40) 1.74 ± 0.38 ND means not detected.

Compared with the AMPC-suspension, both AMPC-containing gastrointestinalmucosa-adherent preparations showed higher anti-HP activity and, inparticular, the AMPC-containing gastrointestinal mucosa-adherentpreparation containing curdlan showed a remarkably superior effect.

EXAMPLE 9

Production of a urease inhibitor-containing gastrointestinalmucosa-adherent preparation

Hydrogenated caster oil (Lubri wax 101™, Freund Industrial Co. Ltd.)(78.0 g) was melted at 84° C. To this melt, 4.0 g of compound-A, 8.0 gof acrylic polymer (HIVISWAKO 104™, Wako Pure Chemical Industries, Ltd.)and 10.0 g of Curdlan (Takeda Chemical Industries, Ltd.) were seriallyadded and the mixture was stirred for dispersion at a constanttemperature of 84° C. for 15 minutes. This molten mixture was droppedonto a 15 cm (di.) aluminum disk rotating at 1950 rpm at a flow rate of10 g/min, whereby 42/60 mesh spherical fine granules were obtained.

EXAMPLE 10

Production of an indolmycin-containing gastrointestinal mucosa-adherentPreparation

Behenic acid hexa (tetra) glyceride (HB-310™ Sakamoto Yakuhin Kogyo Co.Ltd.)(60.0 g) was melted at 80° C. To this melt, 30.0 g of indolmycin,6.0 g of acrylic polymer (HIVISWAKO 104™, Wako Pure Chemical Industries,Ltd.) and 4.0 g of low substituted hydroxypropylcellulose (LH-31™,Shin-Etsu Chemicals) were serially added and the mixture was stirred fordispersion at a constant temperature of 80° C. for 2 hours. This moltenmixture was dropped onto a 15 cm (di.) aluminum disk rotating at 3960rpm at a flow rate of 50 g/min, whereby spherical fine granules passingthrough a 42-mesh (hereinafter referred to briefly as 42-mesh pass) wereobtained.

EXAMPLE 11

Production of an indolmycin-containing gastrointestinal mucosa-adherentpreparation

Behenic acid hexa (tetra) glyceride (HB-310™, Sakamoto Yakuhin Kogyo Co.Ltd.)(55.0 g) was melted at 80° C. To this melt, 35.0 g of indolmycin,6.0 g of acrylic polymer (HIVISWAKO 104™, Wako Pure Chemical Industries,Ltd.) and 4.0 g of low substituted hydroxypropylcellulose (LH-31™,Shin-Etsu Chemicals) were serially added and the mixture was stirred fordispersion at a constant temperature of 80° C. for 2 hours. This moltenmixture was dropped onto a 15 cm (di.) aluminum disk rotating at 3960rpm at a flow rate of 50 g/min, whereby 42-mesh pass spherical finegranules were obtained.

EXAMPLE 12

Production of an indolmycin-containing gastrointestinal mucosa-adherentpreparation

A mixture of hydrogenated castor oil (Lubri wax 101™, Freund IndustrialCo. Ltd.) (40.0 g) and behenic acid hexa (tetra) glyceride (HB-310™,Sakamoto Yakuhin Kogyo Co. Ltd.)(30.0 g) was melted at 85° C. To thismelt, 10.0 g of indolmycin, 10.0 g of acrylic polymer (HIVISWAKO 104™,Wako Pure Chemical Industries, Ltd.) and 10.0 g of low substitutedhydroxypropylcellulose (LH-31™, Shin-Etsu Chemicals) were serially addedand the mixture was stirred for dispersion at a constant temperature of85° C. for 2 hours. This molten mixture was dropped onto a 15 cm (di.)aluminum disk rotating at 2700 rpm at a flow rate of 50 g/min, whereby42/119-mesh pass spherical fine granules were obtained.

EXAMPLE 13

Production of an indolmycin-containing gastrointestinal mucosa-adherentpreparation

Behenic acid hexa (tetra) glyceride (HB-310™, Sakamoto Yakuhin Kogyo Co.Ltd.)(87.0 g) was melted at 80° C. To this melt, 1.0 g of indolmycin,8.0 g of acrylic polymer (HIVISWAKO 104™, Wako Pure Chemical Industries,Ltd.) and 4.0 g of low substituted hydroxypropylcellulose (LH-31™,Shin-Etsu Chemicals) were serially added and the mixture was stirred fordispersion at a constant temperature of 80° C. for 2 hours. This moltenmixture was dropped onto a 15 cm (di.) aluminum disk rotating at 2400rpm at a flow rate of 50 g/min, whereby 42-mesh pass spherical finegranules were obtained.

EXAMPLE 14

Production of an indolmycin-containing qastrointestinal mucosa-adherentpreparation

Behenic acid hexa (tetra) glyceride (HB-310™, Sakamoto Yakuhin Kogyo Co.Ltd.) was melted at 80° C. This melt was dropped onto a 15 cm (di.)aluminum disk rotating at 1800 rpm at a flow rate of 50 g/min, whereby42/119 mesh spherical fine granules were obtained. Indolmycin (250 g),acrylic polymer (HIVISWAKO 104™, Wako Pure Chemical Industries, Ltd.),(50 g) and low substituted hydroxypropylcellulose (LH-31™, Shin-EtsuChemicals)(50 g) were mixed for 1 min in High Speed Mixer. To thismixture, 150 g of the fine granules were added and stirred at a constanttemperature of 70° C. at 500 rpm, whereby 42-mesh pass spherical finegranules were obtained.

EXAMPLE 15

Production of an indolmycin-containing gastrointestinal mucosa-adherentpreparation

A mixture of behenic acid hexa (tetra) glyceride (HB-310™, SakamotoYakuhin Kogyo Co. Ltd.)(59.5 g) and ricinoleic acid poly (tetra)glyceride (CRS-75, Sakamoto Yakuhin Kogyo Co. Ltd.)(0.5 g) was melted at80° C. To this melt, 30.0 g of indolmycin, 6.0 g of acrylic polymer(HIVISWAKO 104™, Wako Pure Chemical Industries, Ltd.) and 4.0 g of lowsubstituted hydroxypropylcellulose (LH-31™, Shin-Etsu Chemicals) wereserially added and the mixture was stirred for dispersion at a constanttemperature of 80° C. for 2 hours. This molten mixture was dropped ontoa 15 cm (di.) aluminum.disk rotating at 3960 rpm at a flow rate of 50g/min, whereby 42-mesh pass spherical fine granules were obtained.

EXAMPLE 16

Production of an indolmycin-containing gastrointestinal mucosa-adherentpreparation

A mixture of hydrogenated caster oil (Lubri wax 101™, Freund IndustrialCo. Ltd.) (40.0 g) and behenic acid hexa (tetra) glyceride (HB-310™,Sakamoto Yakuhin Kogyo Co. Ltd.)(30.0 g) was melted at 85° C. To thismelt, 10.0 g of indolmycin, 10.0 g of acrylic polymer (HIVISWAKO 104™,Wako Pure Chemical Industries, Ltd.) and 10.0 g of low substitutedhydroxypropylcellulose (LH-31™, Shin-Etsu Chemicals) were serially addedand the mixture was stirred for dispersion at a constant temperature of85° C. for 2 hours. This molten mixture was dropped onto a 15 cm (di.)aluminum disk rotating at 3960 rpm at a flow rate of 50 g/min, whereby42/119-mesh spherical fine granules were obtained.

EXAMPLE 17

Production of an indolmycin-containing gastrointestinal mucosa-adherentpreparation

A mixture of hydrogenated caster oil (Lubri wax 101™, Freund IndustrialCo. Ltd.) (40.0 g) and behenic acid hexa (tetra) glyceride (HB-310™,Sakamoto Yakuhin Kogyo Co. Ltd.)(30.0 g) was melted at 85° C. To thismelt, 10.0 g of indolmycin, 10.0 g of acrylic polymer (HIVISWAKO 104™,Wako Pure Chemical Industries, Ltd.) and 10.0 g of low substitutedhydroxypropylcellulose (LH-22, Shin-Etsu Chemicals) were serially addedand the mixture was stirred for dispersion at a constant temperature of85° C. for 2 hours. This molten mixture was dropped onto a 15 cm (di.)aluminum disk rotating at 3960 rpm at a flow rate of 50 g/min, whereby42/119-mesh spherical fine granules were obtained.

EXAMPLE 18

Production of an indolmycin-containing gastrointestinal mucosa-adherentpreparation

A mixture of hydrogenated caster oil (Lubri wax 101™, Freund IndustrialCo. Ltd.) (40.0 g) and behenic acid hexa (tetra) glyceride (HB-310™,Sakamoto Yakuhin Kogyo Co. Ltd.)(30.0 g) was melted at 85° C. To thismelt, 10.0 g of indolmycin, 10.0 g of acrylic polymer (HIVISWAKO 104™,Wako Pure Chemical Industries, Ltd.) and 10.0 g of Curdlan (TakedaChemical Industries, Ltd.) were serially added and the mixture wasstirred for dispersion at a constant temperature of 85° C. for 2 hours.This molten mixture was dropped onto a 15 cm (di.) aluminum diskrotating at 3960 rpm at a flow rate of 50 g/min, whereby 42/119-meshspherical fine granules were obtained.

Comparative Example 2

Production of an indolmycin-containing gastrointestinal mucosa-adherentpreparation

A mixture of hydrogenated caster oil (Lubri wax 101™, Freund IndustrialCo. Ltd.) (40.0 g) and behenic acid hexa (tetra) glyceride (HB-310™,Sakamoto Yakuhin Kogyo Co. Ltd.)(30.0 g) was melted at 85° C. To thismelt, 10.0 g of indolmycin, 10.0 g of acrylic polymer (HIVISWAKO 104™,Wako Pure Chemical Industries, Ltd.) and 10.0 g of partly pregelatinizedstarch (PCS, Asahi Kasei Industries, Ltd.) were serially added and themixture was stirred for dispersion at a constant temperature of 85° C.for 2 hours. This molten mixture was-dropped onto a 15 cm (di.) aluminumdisk rotating at 3960 rpm at a flow rate of 50 g/min, whereby42/119-mesh spherical fine granules were obtained.

Comparative Example 3

Production of an indolmycin-containing gastrointestinal mucosa-adherentpreparation

A mixture of hydrogenated caster oil (Lubri wax 101™, Freund IndustrialCo. Ltd.) (40.0 g) and behenic acid hexa (tetra) glyceride (HB-310™,Sakamoto Yakuhin Kogyo Co. Ltd.)(30.0 g) was melted at 85° C. To thismelt, 10.0 g of indolmycin, 10.0 g of acrylic polymer (HYIVISWAKO 104™,Wako Pure Chemical Industries, Ltd.) and 10.0 g of hydroxypropyl starch(HPS, Freund Industrial Co. Ltd.) were serially added and the mixturewas stirred for dispersion at a constant temperature of 85° C. for 2hours. This molten mixture was dropped onto a 15 cm (di.) aluminum diskrotating at 3960 rpm at a flow rate of 50 g/min, whereby 42/119-meshspherical fine granules were obtained.

Test Example 3

In vivo anti-Helicobacter pylori effect of the indolmycin-containinggastrointestinal mucosa-adherent preparation

Mice (Crj: ICR) infected with HP were orally dosed with theindolmycin-containing gastrointestinal mucosa-adherent preparationobtained in Example 16,17 and 18 (IDM-AdMMS-16, -17 and -18 in Table 3),the indolmycin-containing gastrointestinal mucosa-adherent preparationobtained in Comparative Example 2 and 3 (IDM-AdMMS-C2 and C3 in Table3), respectively at a dose of 30 mg/kg as indolmycin twice a day for oneday. At 16 hours after the final dose, the stomach was excised and thegastric wall was homogenized and serial dilutions were plated on the HPselective medium. The inoculated medium was incubated for 4 days at 37°C. under microaerobic conditions and the number of viable cells wascounted. The results are shown in Table 3.

TABLE 3 Clearance rate Dose (mg/kg) Cleared/total Formulation Indolmycin(%) IDM-AdMMS-C2 30 0/6 (0) IDM-AdMMS-C3 30 0/6 (0) IDM-AdMMS-16 30 2/6(33) IDM-AdMMS-17 30 1/7 (14) IDM-AdMMS-18 30 4/11 (36)

Compared with the IDM-containing gastrointestinal mucosa-adherentpreparation containing PCS and HPS-101, IDM-containing gastrointestinalmucosa-adherent preparations containing LH-31™, LH-22 and curdlan showedhigher anti-HP activity.

Test Example 4

In vivo anti-Helicobacter pylori effect of the indolmycin-containinggastrointestinal mucosa-adherent preparation

Mongolian gerbils (MON/Jms/Gbs) infected with HP were orally dosed withindolmycin-containing gastrointestinal mucosa-adherent preparationobtained in Example 13 (IDM-AdMMS-13 in Table 4) or a 0.5%methylcellulose suspension containing indolmycin (IDM-suspension inTable 4), respectively at a dose of 1 mg/kg as indolmycin for AdMMS or10 mg/kg as indolmycin for the suspension twice a day for seven days. At16 hours after the final dose, the stomach was excised and the gastricwall was homogenized and serial dilutions were plated on the HPselective medium. The inoculated medium was incubated for 4 days at 37°C. under microaerobic conditions and the number of viable cells wascounted. The results are shown in

TABLE 4 Clearance rate Dose (mg/kg) Cleared/total Formulation Indolmycin(%) Control 0 0 IDM- 10 100 suspension IDM-AdMMS-13 1 100

The indolmycin-containing gastrointestinal mucosa-adherent preparationshowed an equivalent anti-HP effect at the dose of one tenth of thesuspension.

Industrial Applicability

The mucosal medication system of the present invention is capable ofattaching itself to the gastric mucosa and/or staying in the stomach torelease an anti-HP agent for a potentiated bacterial elimination andexterminating action so that it is of great use in the treatment of H.pylori infections. Moreover, it is useful for the prophylaxis andtherapy of various gastrointestinal diseases associated with H. pylori(e.g. gastritis, gastric ulcer, duodenal ulcer, etc.).

What is claimed is:
 1. A gastrointestinal mucosa-adherent pharmaceuticalcomposition comprising (A) a polyglycerol fatty acid ester, a lipid or acombination thereof, (B) a viscogenic agent, (C) low-substitutedhydroxypropylcellulose and (D) an active ingredient, wherein saidlow-substituted hydroxypropylcellulose is contained in the range ofabout 1 to 30 weight %, relative to the total weight of the compositionwhich is an effective gastrointestinal mucosa-adherent pharmaceuticalcomposition.
 2. A pharmaceutical composition according to claim 1, whichis a matrix comprising a polyglycerol fatty acid ester, a lipid or acombination thereof.
 3. A pharmaceutical composition according to claim2, wherein said low-substituted hydroxypropylcellulose is dispersed. 4.A pharmaceutical composition according to claim 3, which is in granuleform.
 5. An anti-Helicobacter pylori pharmaceutical compositioncomprising (A) a polyglycerol fatty acid ester, a lipid or a combinationthereof, (B) a viscogenic agent, (C) low-substitutedhydroxypropylcelullose and (D) an effective amount of ananti-Helicobacter pylori substance, wherein said low-substitutedhydroxypropylcellulose is contained in the range of about 1 to 30 weight%, relative to the total weight of the composition which is an effectivegastrointestinal mucosa-adherent pharmaceutical composition.
 6. Anantimicrobial pharmaceutical composition comprising (A) a polyglycerolfatty acid ester, a lipid or a combination thereof, (B) a viscogenicagent, (C) low-substituted hydroxypropylcellulose and (D) an effectiveamount of an antimicrobial substance, wherein said low-substitutedhydroxypropylcellulose is contained in the range of about 1 to 30 weight%, relative to the total weight of the composition which is an effectivegastrointestinal mucosa-adherent pharmaceutical composition.
 7. Apharmaceutical composition according to claim 1, wherein thehydroxypropoxy content of the low-substituted hydroxypropylcellulose isabout 7.0 to about 13.0%.
 8. A pharmaceutical composition according toclaim 2, wherein the lipid is a hydrogenated castor oil.
 9. Apharmaceutical composition according to claim 2, wherein thepolyglycerol fatty acid ester is an ester of a polyglycerol having adegree of polymerization from 2 to 20 with a fatty acid containing 12 to22 carbon atoms.
 10. A pharmaceutical composition according to claim 2,wherein the used amount of the polyglycerol fatty acid ester and/or thelipid is 20 to 95 weight % to the total weight of the composition.
 11. Apharmaceutical composition according to claim 2, wherein the used amountof the polyglycerol fatty acid ester and/or the lipid is 0.1 to 100times by weight to the active ingredient in the composition.
 12. Apharmaceutical composition according to claim 2, comprising a viscogenicagent in the matrix.
 13. A pharmaceutical composition according to claim11, wherein the used amount of the viscogenic agent is 0.5 to 30 weight% to the used weight of the composition.
 14. A pharmaceuticalcomposition according to claim 2, wherein the HLB number of thepolyglycerol fatty acid ester is about 1 to about
 9. 15. Apharmaceutical composition according to claim 5, wherein the used amountof the anti-Helicobacter pylori substance is 10 to 50 weight % to thetotal weight of the composition.
 16. A pharmaceutical compositionaccording to claim 2, wherein the matrix is coated with a coatingmaterial comprising a viscogenic agent.
 17. A pharmaceutical compositionaccording to claim 12 or 16, wherein the viscogenic agent is an acrylicpolymer or salt thereof.
 18. A pharmaceutical composition according toclaim 5, wherein the anti-Helicobacter pylori substance is amoxicillin.19. A pharmaceutical composition according to claim 5, wherein theanti-Helicobacter pylori substance isN-(diaminophosphinyl)-5-methyl-2-thiophenecarboxamide.
 20. Apharmaceutical composition according to claim 5, wherein theanti-Helicobacter pylori substance is a tryptophanyl-t-RNA synthesisinhibitor.
 21. A pharmaceutical composition according to claim 5,wherein the anti-Helicobacter pylori substance is a oxazolonederivative.
 22. A pharmaceutical composition according to claim 5,wherein the anti-Helicobacter pylori substance is indolymycin.
 23. Amethod to accelerate gastrointestinal mucosa-adherent activity of apharmaceutical composition comprising adding low-substitutedhydroxypropylcellulose to a pharmaceutical composition composition of aviscogenic agent and an active ingredient.
 24. A method for modulatingthe adherence of a gastrointestinal mucosa-adherent composition, saidmethod comprising adding low-substituted hydroxypropylcellulose as anaccelerant of gastrointestinal mucosa-adherent activity to agastrointestinal mucosa-adherent composition of a viscogenic agent andan active ingredient.
 25. A pharmaceutical composition according toclaim 2, comprising (i) low-substituted hydroxypropylcellulose, (ii)acrylic polymer or salt thereof, (iii) polyglycerol fatty acid ester,lipid or a combination thereof and (iv) an anti-Helicobacter pylorisubstance.
 26. A pharmaceutical composition according to claim 25,wherein (i) the hydroxypropoxy content of said low-substitutedhydroxypropylcellulose is about 7.0 to about 13.0%, (ii) the molecularweight of the acrylic polymer is about 20×10⁴ to about 600×10⁴, (iii)the polyglycerol fatty acid ester is tetraglycerol polyricinolate, and(iv) the anti-Helicobacter pylori substance is indolmycin.
 27. Apharmaceutical composition according to claim 2, comprising (i) about 1to about 20 parts by weight of said low-substitutedhydroxypropylcellulose, whose hydroxypropoxy content is about 7.0 toabout 13.0%, (ii) about 1 to about 20 parts by weight of acrylic polymeror salt thereof, whose molecular weight is about 20×10⁴ to about600×10⁴, (iii) about 40 to about 90 parts by weight of behenic acidhexa(tetra)glyceride, tetraglycerol polyricinolate or a combinationthereof, and (iv) about 5 to about 40 parts by weight of indolmycin.